I. Field of the Invention
This invention relates to a process for the production of streptovaricin C.
II. Description of the Prior Art
U.S. Pat. No. 3,116,202 describes streptovaricins and their production. As disclosed therein, Streptomyces spectabilis (NRRL2494) produces five types of streptovaricins designated as types A, B, C, D, and E. It also describes the use of streptovaricin as an antituberculosis drug. However, this product has not achieved broad use for this purpose.
Example 3 of this patent discloses the accumulation of 21 mg/l of streptovaricin in the broth assuming that the crude product was 100% pure. However, the disclosure gives no indication of the amount or ratio of streptovaricin C in the crude mixture.
More recent attempts have been made to obtain novel antibiotics by chemically modifying streptovaricin C in order to provide anti-virus and anti-cancer agents (See K. Sasaki, T. Naito, T. Satomi, and K. Onodera, The Journal of Antibiotics, Feb. 1976, pp.147-154). (See S. Ito, N. Yamamota, K. Nomoto, K. Sasaki, and K. Onodera, The Journal of Antibiotics, May 1989, pp.779-787.)
These derivatives use only streptovaricin C and thus require a method for selectively preparing streptovaricin C. In the May 1989, K. Onodera et al article, the yield of streptovaricin C, the most abundant component of the streptovaricin complex provided by the Upjohn Co. and used by the authors, was about 20%. (See pages 151-152).
In K. Rinehart et al., Biochemistry, Vol. 13, No. 5, 1974, pp. 861-867, the content of streptovaricin C within the mixture of streptovaricins obtained from the provider (Upjohn 11560-3), was about 10 to 20%. This suggests that the streptovaricin C content in the broth of Example 3 of U.S. Pat. No. 3,116,202, was about 2-4 mg/L. These amounts and concentrations are not sufficient for further development of streptovaricin C derivatives.
A more efficient method for separating streptovaricin C from a culture broth of a streptovaricin producing strain which produces a mixture of types A, B, C, D and E, is disclosed in Japanese applications No. 14285/1990 and 14286/1990 corresponding to U.S. patent application Ser. No. 07/601,875, filed Oct. 23, 1990. (See also H. Wang, Annals New York Academy of Sciences, 431, 1983, pp. 313-321.) In these methods, a publicly available streptovaricin-producing strain (ATCC 27465) is cultured in the presence of a non-ionic adsorbent and with the optional addition of fumaric acid or one of its water-soluble salts. Using these methods, it was possible to increase the amount of streptovaricin C separated from the culture broth. Even so, higher productivity of streptovaricin is needed for proper development and commercial production of this compound.